title: Diacylglycerol lipase α manipulation reveals developmental roles for intercellular endocannabinoid signaling.
abstract: Endocannabinoids are small signaling lipids, with 2-arachidonoylglycerol (2-AG) implicated in modulating axonal growth and synaptic plasticity. The concept of short-range extracellular signaling by endocannabinoids is supported by the lack of trans-synaptic 2-AG signaling in mice lacking sn-1-diacylglycerol lipases (DAGLs), synthesizing 2-AG. Nevertheless, how far endocannabinoids can spread extracellularly to evoke physiological responses at CB₁ cannabinoid receptors (CB₁Rs) remains poorly understood. Here, we first show that cholinergic innervation of CA1 pyramidal cells of the hippocampus is sensitive to the genetic disruption of 2-AG signaling in DAGLα null mice. Next, we exploit a hybrid COS-7-cholinergic neuron co-culture system to demonstrate that heterologous DAGLα overexpression spherically excludes cholinergic growth cones from 2-AG-rich extracellular environments, and minimizes cell-cell contact in vitro. CB₁R-mediated exclusion responses lasted 3 days, indicating sustained spherical 2-AG availability. Overall, these data suggest that extracellular 2-AG concentrations can be sufficient to activate CB₁Rs along discrete spherical boundaries to modulate neuronal responsiveness.
authors.affiliation: Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Keimpema
authors.forename: Alán
authors.initials: A
authors.lastname: Alpár
authors.forename: Fiona
authors.initials: F
authors.lastname: Howell
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Malenczyk
authors.forename: Carl
authors.initials: C
authors.lastname: Hobbs
authors.forename: Yasmin L
authors.initials: YL
authors.lastname: Hurd
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kano
authors.forename: Patrick
authors.initials: P
authors.lastname: Doherty
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D018920:Coculture Techniques; D063388:Endocannabinoids / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; C094503:glyceryl 2-arachidonate; D008071:Lipoprotein Lipase